Abstract
The Genetic Analysis Workshop (GAW) presents an opportunity to collaboratively evaluate methodology relevant to current issues in genetic epidemiology. The GAW20 data combine real clinical trial data with fictitious epigenetic drug response endpoints. Considering the evidence suggesting that networks of interactions between many genes underlie complex phenotypes, we utilize differential methylation status to identify a relevant gene set for enrichment analysis and use this to infer potential biological function underlying drug response. We highlight the pertinence of considering the potential for widespread epistatic interactions in the absence of main effects, and present evidence of epistasis between single-nucleotide polymorphisms (SNPs) on the two RNA demethylases FTO and ALKBH5.
Highlights
The Genetic Analysis Workshop (GAW) is a forum for investigators to develop and critique new analytical methods for complex traits on a shared data set
The GAW20 data provide simulated replications based on the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) clinical trial, had participants been subject to treatment with a fictitious drug with a pharmacoepigenetic effect on triglyceride response [1]
Analysis of the real data was performed following GAW attendance, as it was revealed that the data simulation methods did not consider interactions, and analysis of interactions in the simulated data was not appropriate
Summary
The GAW is a forum for investigators to develop and critique new analytical methods for complex traits on a shared data set. The GAW20 data provide simulated replications based on the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) clinical trial, had participants been subject to treatment with a fictitious drug with a pharmacoepigenetic effect on triglyceride response [1]. These data present a unique analysis opportunity as all phenotypes, subject covariates, genotypes, pre-treatment methylation levels, etc. Strategies for better detecting these interactions can aim to avoid exhaustively testing each potential interaction via data reduction methods, integrating expert knowledge, and/or consolidating multiple sources of evidence to narrow the search space [3,4,5]
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